Peter K. Law previously demonstrated that myoblast transfer in Duchenne muscular dystrophy (DMD) muscles produced dystrophin (a protein), and that myoblast transfer in heart muscle produced heavy myosin (another protein). Related patents and publications including Ye et al. 2009 (Diabetologia 52:1925-1934 “Skeletal myoblast transplantation . . . ”) focused on determining the safety and efficacy of treating muscular dystrophies, heart muscle degeneration and diabetes.
These works relied on increased muscle strength, more myofibers, better cell structure and protein replenishment as monitoring end-points. However, they did not identify any underlying genetic/biochemical mechanism that could be used to improve therapy or used as tools for identification and selection of prophylactic or therapeutic agents such as cell transplant agents or lead drug compounds. In contrast these studies indicated that their effects operated via donor cell survival, development and functioning per se. Gene transcription and translation leading towards genetic repair have not been seriously addressed in the clinical prophylaxis and treatment of disease.
One important disease is diabetes. Diabetes is a leading cause of kidney failure and non-traumatic lower-limb amputations among adults in the world. In 2010, the United States was estimated to have spent $198 billion on diabetes treatment1. An estimated 285 million adults had Type II diabetes making up about 90% of diabetes cases in 20102. Diabetes affects ˜25% of western populations, steadily increases3, and is an important cardiovascular disease risk factor4. Epidemiological and twin studies have clearly indicated a major polygenetic factor in the development of insulin resistance, a key feature of Type II diabetes, which was influenced also by environmental factors5,6.
Previous studies demonstrated the importance of skeletal muscles in the development of insulin resistance. Mice with muscle-specific Glut-4 knockout were insulin resistant and glucose-intolerant from an early age7. An isolated defect in protein kinase C-λ, in muscle would induce abdominal obesity and other metabolic abnormalities8. In contrast, muscle-specific LKB1 (a serine/threonine kinase that is a negative regulator of insulin sensitivity) knockout increased insulin sensitivity and improved glucose homeostasis9. These studies suggest that defects in skeletal muscle glucose transport may be key factors in the development of insulin resistance.
Attenuated hyperglycemia and hyperinsulinemia, and improved glucose tolerance of KK mouse occurred with xeno-transplantation of human skeletal myoblasts (hSkMs)10. Skeletal myoblasts are mononucleated, muscle precursor cells capable of fusing with muscle fibers of different types and developing into the host phenotype11. Through natural fusion with KK mouse skeletal muscle fibers, implanted human myoblasts formed hybrid muscle fibers in KK mouse.
Despite this work done with diabetes, no one has identified any underlying gene transcript alterations of multiple genes or genomes. In fact, the teachings and conclusions of those works indicated that any improvement found could all be a result of donor cell survival, development and functioning without genetic repair. Accordingly, any new information and treatment modalities in this area that go beyond this basic knowledge can provide immeasurable benefit to clinical prophylaxis and treatment of disease.